Acta Pharmacologica Sinica (2013) 34: 329–335 npg © 2013 CPS and SIMM All rights reserved 1671-4083/13 www.nature.com/aps Perspective hERG channel function: beyond long QT Joseph J BABCOCK, Min LI* Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine, Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA To date, research on the human ether-a-go-go related gene (hERG) has focused on this potassium channel’s role in cardiac repolar- ization and Long QT Syndrome (LQTS). However, growing evidence implicates hERG in a diversity of physiologic and pathological pro- cesses. Here we discuss these other functions of hERG, particularly their impact on diseases beyond cardiac arrhythmia. Keywords: long QT; hERG; cardiotoxicity; cancer; potassium channel Acta Pharmacologica Sinica (2013) 34: 329–335; doi: 10.1038/aps.2013.6 Introduction other potassium channels, KCNQ1, Kir2.1 (KCNJ2) (both also The human ether-a-go-go related gene (hERG) encoded potas- expressed in the heart and genetically linked to LQTS) and sium channel has generated considerable scientific interest hEAG (an EAG family member also expressed in cancers). due to its role in genetically and pharmacologically linked Compared to Kir2.1 and hEAG, hERG is twice and four times, arrhythmias[1, 2]. Admittedly, promiscuous block of cardiac respectively, more broadly expressed across tissues, tumors, hERG channels by a variety of structurally different drugs rep- and developmental stages. Importantly, KCNQ1 also exhibits resents a major research question and a therapeutic challenge, similar levels of expression to hERG in these three EST profile which has profound impacts on human health. However, its sets. We also caution that these data may represent a conser- initial discovery was prompted not by cardiac phenomena vative estimate, as some examples of negative expression in but by a neurologic phenotype in Drosophila, in which muta- the hERG EST profile, such as breast tumors, contradict exist- tion of the homologous Eag gene leads to spasmodic leg ing functional evidence in these cells[8, 9]. move­ments[3, 4]. Judging by the number of PubMed articles We also explored information concerning differential obtained by a search for ‘hERG’ and ‘heart’ (627) in compari- expression (DE, significant up- or down-regulation), accord- son to ‘cancer’ (107), ‘brain’ (92), or ‘pancreas’ (4), function of ing to microarray and RNA-Seq meta-analyses in the EBI Gene the channel in the nervous system is but one of many topics Expression Atlas[10]. The results in Figure 1B, like the Unigene less prevalent than Long QT Syndrome (LQTS) research. In profiles, indicate a diversity of tissues and diseases in which this perspective we survey existing evidence for hERG expres- hERG is differentially expressed. Intriguingly, even though sion and function in the other tissues, many of which are the metric compared (absence/presence versus DE) is differ- linked to disease. Whether its roles are causal or not, these ent in the Unigene EST and EBI Gene Atlas data, the relation- suggest therapeutic opportunities beyond the cardiac system. ship between the hERG, KCNQ1, Kir2.1, and hEAG profiles remains similar. While hERG and KCNQ1 demonstrate simi- Surveying hERG gene expression lar levels of DE across all samples types, Kir2.1 and hEAG To examine primary evidence for hERG expression in non- have fewer observed cases of DE in the same rank order as cardiac tissues, we utilized NCBI Unigene EST profiles[5]. the EST data. While a more systematic analysis is outside the Previous analyses have suggested that this type of dataset con- scope of this article, we speculate that the similarity in patterns tains fewer false negatives than microarrays[6, 7], an appealing between the presence/absence (EST profiles) and DE (Gene characteristic for a broad survey. The results are displayed in Atlas) data might be explained by more broadly expressed Figure 1A, which compares hERG expression to that of three genes possessing greater ‘opportunity’ for modulation in vari- ous diseases or physiological processes. * To whom correspondence should be addressed. For each of the tissue types annotated for hERG expres- E-mail [email protected] sion by the EST profile, additional existing evidence through Received 2012-12-07 Accepted 2012-01-19 expression, functional studies, or pathologic links are summa- npg www.nature.com/aps Babcock JJ et al 330 non-neoplastic cells when incorporated in the cell membrane, a feedback mechanism that thus exerts pleiotropic effects through vesicular trafficking[22]. In some cancer cell lines, the pharmacological cross-reac- tivity of hERG and other targets complicates interpretation of its function. This is demonstrated by experiments using MCF-7 breast cancer cells, in which application of the selective inhibitor E4031 has identified a distinct role for hERG in vol- ume regulation that is separate from the proliferation medi- ated by the closely related human ether-a-go-go gene (hEAG) potassium channel[9]. These proliferative effects are blocked by astemizole[9], which is known to inhibit both hEAG and hERG, while caspase-3 dependent apoptosis may be initiated by the similarly nonspecific effects of arsenic trioxide[8]. Taken together with previous evidence that associates genetically linked LQTS with mutations in at least eleven genes, includ- ing other potassium, calcium, and sodium channels[47, 48], such data suggest that compounded effects on hERG and other ion-conductive proteins might not be easily separated with Figure 1. Diversity of tissue expression and regulation of cardiac nonselective modulators. Indeed, blockade of multiple classes potassium channels. A) The fraction of samples expressing (gene of ion channels may have synergistic effects on tumor growth, present/absent) hERG (KCNH2), KCNQ1, Kir2.1 (KCNJ2), or hEAG (KCNH1) as suggested by prostate cancer experiments in which amio- channels in Unigene EST profiles for tissues, tumors, and developmental darone (a K+, Ca2+, and Na+ channel blocker) is more potent stages. Parentheses indicate the number of samples in each profile than compounds that block only two ion channel classes[49]. class. B) The number of EBI Gene Expression Atlas experiments Furthermore, natural products such as berberine are thought showing differential expression (transcript regulated up/down) of cardiac to have effects not only on multiple ion fluxes, but also on potassium channels across five experimental classes. other oncogenic pathways[50], thereby complicating the inter- pretation of their anti-migratory activity in hERG-expressing rized in Table 1. AML cells[23]. Additionally, hERG functions in one tissue may be associated with different channels in others. Indeed, Roles in cancer in medullablastomas similar volume regulation, as discussed In addition to signaling in the mammalian nervous system, above, has been linked to the EAG2 channel rather than growing evidence shows changes in membrane potential occur hERG[51]. Conversely, the specific inhibitors E4031 and WAY during cellular differentiation and cell cycle progression[45, 46]. have been shown to mediate apoptotic and anti-proliferative Thus, it is perhaps unsurprising that changes in the expression effects in leukemia, effects that appear independent of hERG in of voltage-sensitive channels such as hERG have been reported other tumors[52]. However, given that the non-selective inhibi- in cancer, a disease associated with disregulated cellular pro- tor ranolazine (which blocks voltage-gated sodium channels[53] liferation. The initial study implicating hERG in oncogenesis as well as hERG[54]) also inhibits leukemia proliferation[55], utilized both Northern blot probes and patch clamps to iden- the effects of blocking multiple ionic currents may be tissue- tify functional expression of the channel in 17 tumor types specific. derived from diverse cell lineages[13]. Because corresponding The particular cell cycle defects associated with hERG non-pathological tissues for these tumors lacked expression of expression may also vary between neoplasms of different hERG, the authors proposed that the depolarization resulting tissue origin. Experiments in gastric and ovarian carcino- from channel over-expression might confer a selective advan- mas suggest that channel function is associated with S-phase tage for survival in hypoxic environments[13]. Additional transition or accumulation[36, 41], while in endometrial cancers functional evidence for this interpretation is that Imatinib (a activity appears to be correlated with occupancy of the G2/M known channel blocker) decreases VEGF secretion in leuke- phase[43]. Cell cycle dependent patterns of channel expression mic cells expressing hERG, which could inhibit the growth add further complexity to hERG’s role in SH-SY5Y neuroblas- of endothelial vasculature that supports tumor viability[21]. toma cells[30]. Furthermore, it remains unclear whether hERG Additional experiments studying pharmacological inhibi- expression in cancerous cells (or nervous system disorders, tion by E4031 (a type III antiarrhythmic and selective channel as discussed below) represents a downstream consequence of blocker) have suggested that hERG expression may facilitate general pathologic processes such as inflammation. Evidence cell migration in diverse hematopoetic neoplasms through an for the modulation of hERG expression by inflammation integrin-associated signaling pathway[17, 19, 23]. Further,